This invention relates to a novel crystalline solid of carvedilol or a solvate thereof, to processes for its preparation, to compositions containing it and to its use in medicine. This invention further relates to a novel process for preparing crystalline carvedilol Form II.
Carvedilol, (xc2x1)-1-(Carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy) ethyl]amino]-2-propanol, is a nonselective xcex2-adrenergic blocker with xcex11-blocking activity. Carvedilol is a racemic mixture having the following structural formula: 
Carvedilol is the active ingredient of COREG(copyright), which is indicated for the treatment of congestive heart failure and for the management of hypertension. Since carvedilol is a multiple-action drug, its beta-blocking activity affects the response to certain nerve impulses in parts of the body. As a result, beta-blockers decrease the heart""s need for blood and oxygen by reducing its workload. Carvedilol is also known to be a vasodilator resulting primarily from alpha-adrenoceptor blockade. The multiple actions of carvedilol are responsible for the antihypertensive efficacy of the drug and for its effectiveness in managing congestive heart failure.
International application No. WO 99/05105 (the ""105 application) discloses that carvedilol can be isolated in two polymorphic forms, depending on the method of preparation. The two polymorphic forms, designated Form I and Form II, are reported to be monotropic and are distinguishable by their infrared, Raman and powder X-ray diffraction (PXRD) spectra. No evidence is found in the literature about the existence of solvate forms of carvedilol.
In Example 1 of the ""105 application, Form I was generated by dissolving crude carvedilol in methanol, heating the solution, cooling the solution, and stirring the solution for a time sufficient to produce Form I. Form II was generated by recrystallizing Form I in 2-propanol.
The present invention relates to the solid state physical properties of carvedilol. These properties can be influenced by controlling the conditions under which carvedilol is obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient""s stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient""s bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. The polymorphic form may give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetric (DSC) and can be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct spectroscopic properties that may be detectable by powder X-ray crystallography, solid state 13C NMR spectrometry and infrared spectrometry.
The present invention also relates to solvates of carvedilol. When a substance crystallizes out of solution, it may trap molecules of solvent at regular intervals in the crystal lattice. Solvation also affects utilitarian physical properties of the solid state like flowability and dissolution rate.
One of the most important physical properties of a pharmaceutical compound, which can form polymorphs or solvates, is its solubility in aqueous solution, particularly the solubility in gastric juices of a patient. Other important properties relate to the ease of processing the form into pharmaceutical dosages, such as the tendency of a powdered or granulated form to flow and the surface properties that determine whether crystals of the form will adhere to each other when compacted into a tablet.
The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. A new polymorphic form and solvate of carvedilol has been discovered.
In one aspect, the present invention provides a crystalline solid of carvedilol or a solvate thereof characterized by data selected from the group consisting of a PXRD pattern with peaks at about 6.5, 7.3, 16.0, and 30.5xc2x10.2 degrees two-theta, a PXRD pattern with peaks at about 5.8, 10.7, 11.1, 11.5, 13.1, 13.7, 16.8, 17.7, 18.5, and 23.0xc2x10.2 degrees two-theta, a DSC thermogram with endothermic peaks at about 74xc2x0 C. and 112xc2x0 C., and a FTIR spectrum with peaks at about 613, 740, 994, 1125, 1228, 1257, 1441, 1508, 1737, 2840, 3281, 3389, and 3470 cmxe2x88x921. Said solid crystalline form denotes Form VI.
In another aspect, the present invention provides a process for preparing a crystalline solid of carvedilol or a solvate thereof having at least one characteristic of Form VI (such as the PXRD peaks and/or FTIR peaks, and/or DSC peaks disclosed herein). In accordance with the process, carvedilol is contacted with ethyl acetate to form a solution. The solution is cooled and optionally seeded with carvedilol Form II. The solution can be stirred under high velocity agitation to form a suspension, which then can be cooled under high velocity agitation.
In yet another aspect, the present invention provides a process for preparing a crystalline solid of carvedilol Form II, including the steps of heating crystalline carvedilol having at least one characteristic of Form VI until the crystalline carvedilol is dry, mixing carvedilol Form II with the dry crystalline carvedilol, and storing the mixture for a holding time sufficient to transform the dry crystalline carvedilol into Form II.